Aberrant protein aggregation is mechanistically linked to the emergence of late-onset human neurodegenerative disorders such as Alzheimer's (AD), Parkinson's (PD) and Huntington's (HD) diseases (Selkoe, 2003, Nature 426(6968):900-4). Although the nature of the aggregating proteins and the mechanisms that underlie the development of these maladies differ greatly, they share surprisingly similar temporal patterns of emergence. Typically, familial, mutation-linked cases emerge during the fifth decade of life while sporadic cases do not onset earlier the seventh decade (Amaducci and Tesco, 1994, Curr. Opin. Neurol. 7(4):283-6). Hitherto it is largely unknown why these disorders onset late in life and why distinct maladies exhibit similar temporal emergence patterns, however recent studies indicate that the aging process plays major roles in enabling the aggregation of neurodegeneration-linked proteins, to onset late in life (Cohen et al., 2006, Science 313(5793):1604-10).
Perhaps the most prominent aging and lifespan regulating pathway is the Insulin/IGF signaling pathway (IIS). IIS reduction elevates stress resistance and extends lifespans of worms, flies (Kenyon, 2005, Cell 120(4):449-60) and mice (Holzenberger et al., 2003, Nature 421(6919):182-7). In the nematode Caenorhabditis elegans (C. elegans), the sole Insulin/IGF receptor DAF-2, initiates a signaling cascade that mediates the phosphorylation of its downstream transcription factor DAF-16. Phosphorylated DAF-16 is prevented from entering the nucleus and from regulating its target genes. Thus, IIS reduction hyper-activates DAF-16 and creates long-lived, stress resistant worms (Kenyon, 2005, Cell 120(4):449-60). Similarly, reduced IGF signaling mediates longevity and stress resistance of mice (Holzenberger et al., 2003, Nature 421(6919):182-7; Taguchi et al. 2007, Science 317(5836):369-72).
The IGF signaling pathway was shown to attenuate in human centenarians of different ethnicities (Suh et al. 2008, Proc. Natl. Acad. Sci 105(9):3438-42; Flachsbart et al. 2009, Proc. Natl. Acad. Sci 106(8):2700-5), suggesting that this longevity mechanism is conserved from worms to humans.
IIS reduction was further found to protect worms from the toxic effects that stem from the expression and aggregation of the human Alzheimer's disease associated peptide, Aβ1-42 in their body wall muscles (Aβ worms) (Cohen et al., 2006, Science, 313(5793):1604-10). It is apparent that the cellular ability to maintain proper protein homeostasis is critical to enable longevity (Cohen and Dillin, 2008, Nature Rev. Neuroscience 9: 759-67). Analogously to worms, long-lived mice that harbor only one copy of the IGF1 receptor (IGF1 receptor is a mammalian DAF-2 orthologue) are protected from behavioral and pathological impairments associated with the aggregation and deposition of human Aβ in the brain. This protection was suggested to be conferred by the formation of densely packed Aβ of low toxicity in the brain (Cohen et al. 2009, Cell 139(6):1157-69). It was further shown that late life IIS reduction efficiently protects from Ab toxicity of transgenic nematodes that express human Aβ without affecting development, reproduction or lifespan (Cohen et al. 2010, Aging Cell 9:126-34). These data indicate that the protection from Aβ proteotoxicity provided by reduced IIS is conserved from worms to mice.
Recent studies indicate that this approach of IIS reduction can protect worm models from toxicity of various neurodegeneration-linked, aggregative proteins including ataxin-3 (Teixeira-Castro et al., Hum Mol Genet. 20(15): 2996-3009) and TDP-43 (Zhang et al., Hum Mol Genet. 15; 20(10):1952-65). WO 2010/075511, to some of the inventors of the present invention, disclosed a study in which genetically engineered Alzheimer's model of mice with reduced IGF-1 signaling were found to be protected from Alzheimer's like disease symptoms, including reduced behavioral impairment, mitigated neuroinflammation, and slower rate of neuronal loss. This protection was correlated with the hyper-aggregation of Aß leading to tightly packed, ordered plaques, suggesting that one aspect of the protection conferred by reduced IGF signaling is the sequestration of highly toxic soluble Aß oligomers into dense aggregates of lower toxicity. Based on these results, it was suggested that agents that reduce IGF-1 signaling may be useful for the treatment of neurodegenerative diseases, yet not a single candidate was identified.
IIS reduction was previously suggested for the treatment of various cell proliferative disorders. Enhanced activities of protein tyrosine kinases resulting from overexpression of the normal kinase, upregulation of ligands of receptor tyrosine kinases or activating mutations, are a hallmark of many diseases which involve cellular proliferation, including cancer. Examples of specific receptor tyrosine kinases associated with cell proliferative disorders include platelet derived growth factor receptor (PDGFR), insulin-like growth factor 1 receptor (IGF-1R), epidermal growth factor receptor (EDFR), and the related HER2.
WO 2008/068751 and WO 2009/147682 to some of the inventors of the present invention discloses the use of tyrphostin derivatives acting as protein kinase (PK) and receptor kinase (RK) signaling modulators for the treatment of diseases associated with altered or abnormal activity or signaling of protein kinases, such as cell proliferative disorders, in particular cancer, diabetic nephropathy, a metabolic disorder, a fibrotic disorder or psoriasis.
There have been several drugs developed for the treatment of Alzheimer's disease, including several anticholinergic agents, which are currently marketed. However, there remains a continuing need for the development of additional therapeutic strategies for the treatment of Alzheimer's disease as well as other neurodegenerative diseases.